LncRNA FEZF1-AS1 promotes the tumorigenesis and suppresses ferroptosis in non-small cell lung cancer through the TNF-α/NF-κB pathway.

[OBJECTIVE] The purpose of this research was to examine the impact of FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) on ferroptosis regulation in non-small cell lung cancer (NSCLC) cells and to understand its molecular mechanism.

[METHODS] The effects of FEZF1-AS1 silencing on NSCLC cell proliferation, invasion, migration, and apoptosis were evaluated through functional assays, utilizing the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, and Transwell assays. The levels of cellular reactive oxygen species, malondialdehyde, glutathione, and Fe were measured using commercial assay kits. Proteins related to ferroptosis and the tumor necrosis factor-alpha (TNF-α)/nuclear factor-κB (NF-κB) axis were analyzed using Western blot. Finally, rescue experiments were carried out by treating the cells with TNF-α.

[RESULTS] FEZF1-AS1 expression was significantly upregulated in NSCLC cells. Moreover, FEZF1-AS1 silencing suppressed proliferation, migration, and invasion, while enhancing ferroptosis sensitivity in NSCLC cell lines. This knockdown also inhibited the TNF-α/NF-κB pathway. TNF-α attenuated both pro-ferroptotic and anti-tumor effects of FEZF1-AS1 silencing in NSCLC cells. Mechanistically, knockdown of FEZF1-AS1 modulates ferroptosis and malignant behaviors in NSCLC cells through suppression of the TNF-α/NF-κB axis.

[CONCLUSION] Our study uncovers a previously unrecognized mechanistic axis in which FEZF1-AS1 promotes NSCLC progression through suppressing ferroptosis by activating the TNF-α/NF-κB axis.